PLoS Pathogens | 2021
Role of inflammasomes/pyroptosis and PANoptosis during fungal infection
Abstract
The innate immune system is essential for recognizing foreign invaders and engaging a cellular and physiological response to control infection. Most human pathogenic fungi are opportunistic and take advantage of immune system defects. The 2 pathogens responsible for the majority of fungal infections in humans, Candida albicans and Aspergillus fumigatus, are no exception. One of the major components of the innate immune system that has critical roles in fighting microbial infections, including fungal infections, is the inflammasome [1,2]. Inflammasomes are multimeric protein platforms that lead to inflammatory caspase-1 activation, which in turn drives proteolytic maturation of proinflammatory cytokines IL-1β and IL-18. Processing of IL1β and IL-18 could also be inflammasome-independent during infections due to host intrinsic proteases, and this has been extensively reviewed elsewhere [3]. Active caspase-1 also parallelly induces the cleavage and activation of gasdermin D (GSDMD), which forms pores in the plasma membrane, leading to a lytic form of inflammatory cell death called pyroptosis and facilitating the extracellular release of IL-1β and IL-18 [4,5]. To date, multiple innate sensors with the potential to assemble inflammasome complexes have been identified, including the nucleotide-binding domain and leucine-rich repeat receptors (NLRs) NLRP1, NLRC4, and NLRP3 as well as absent in melanoma 2 (AIM2) and pyrin [1]. Inflammasomes are activated when the sensor recognizes pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). In the context of fungal infection, polysaccharides, which are the major component of the fungal cell wall, serve as a large source of fungal PAMPs. Cell wall-purified zymosan and mannan were the first fungal ligands shown to activate the canonical NLRP3 inflammasome [6]. While several fungal species are now known to be capable of activating inflammasomes, including C. albicans, A. fumigatus, Cryptococcus neoformans, Paracoccidioides brasiliensis, Malassezia spp., and Microsporum canis, among others [7–13], the full range of fungal PAMPs responsible for inflammasome activation remains a key topic of study for several of these pathogens. Growing understanding of the physiological importance of inflammasomes in antimicrobial defense has resulted in the rapid exploration of fungi-induced inflammasome activation [6,14,15]. Initial studies focused on the role of the IL-1 family cytokines IL-1β and IL-1α in restricting the fungal pathogen C. albicans during systemic infection have provided convincing evidence for the role of inflammasomes in antifungal immunity [14]. Similarly, mice lacking IL-1β and/or IL-18, the 2 inflammasome-dependent effector cytokines, are susceptible to aspergillosis [15]. Here, we focus on the molecular mechanisms of inflammasome activation